Miniature swine, because of their size, physiological similarity to humans, breeding characteristics and availability, are an attractive potential donor for clinical xenotransplantation. However, the study of an acceptable model in which the human anti-pig response can be evaluated directly in vivo. A mouse model to study rejection of pig skin grafts by human peripheral blood cells has been developed in this laboratory. RAG-1 (recombinase activating gene-1) mutant mice (R), lacking both mature B and T cells are able to accept porcine skin grafts indefinitely with the need of immunosuppression. R-mice engrafted with porcine skin grafts and reconstituted with human peripheral blood cells (Hu-R), as a model of the human immune system, were found to be capable of rejecting the porcine skin grafts. The pathological changes observed within rejecting grafts were remarkably similar to those seen in primate anti-porcine xenograft rejection, and can be mediated by purified human CD4 T cells. The major goal of this proposal is to study the mechanism of the human anti-porcine cellular xenograft response in vivo utilizing this Hu-R mouse model. The specific aims are to: 1) Determine whether human CD8 T cells and natural killer (NK) cells participate in pig xenografts; 3) Determine the relative importance of pig major histocompatibility (MHC) class I and class I antigen recognition by human T cells in the anti-pig response; and 4) Determine the effect of blocking the interactions between adhesion molecules expressed on human leukocytes and pig endothelium on xenograft rejection. The development and characterization of a small animal model to study cellular immune responses of human cells to discordant xenografts in vivo, will provide a convenient means to ask mechanistic questions of importance to the field of xenotransplantation, and provide a practical system in which approaches to prevent rejection of xenografts can be tested directly.